PROJECT SUMMARY Salmonellae are Enterobacteriaceae that cause a spectrum of diseases in humans and animals, including enteric (typhoid) fever and gastroenteritis. Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), results in a life-threatening systemic disease that is responsible for significant morbidity and mortality annually worldwide. The disease is endemic in many parts of Africa, including Kenya. 1-5% of individuals infected with S. Typhi become chronic carriers with the gallbladder (GB) as the site of persistence. S. Typhi is a human-restricted pathogen, therefore asymptomatic carriers represent a critical reservoir for further spread of disease. We have demonstrated that gallstones (GSs) aid in the development and maintenance of GB carriage in a mouse model and in humans, serving as a substrate to which salmonellae attach and form a protective biofilm. However, the epidemiology regarding the development of Salmonella chronic carriage and spread of the disease from both acute and chronic carriers is poorly understood. In this proposal, we intend to prospectively study a population in a typhoid fever endemic region in Kenya to better understand: (1) genomics, antibiotic resistance and biofilm phenotypes of the S. Typhi strains causing typhoid fever and chronic carriage, (2) the linkage of GSs to the establishment of chronic carriers, and (3) the local epidemiology and geospatial distribution of typhoid fever in the target urban community. Modeling the data gathered will allow a greater understanding of the strains causing acute and chronic infection and the associated epidemiologic factors contributing to S. Typhi spread in a community. This will also help healthcare practitioners better treat and predict the likelihood of disease transmission as well as asymptomatic carriage.